Disordered phosphorus and vitamin D metabolism are novel risk factors for cardiovascular disease (CVD) and mortality in patients with chronic kidney disease (CKD), a public health epidemic estimated to affect 20 million people in the US. Fibroblast growth factor-23 (FGF-23) is a recently discovered hormone that regulates serum phosphate and 1, 25-dihydroxyvitamin D (1,25D) levels. The most common disorder of FGF-23 excess is CKD in which progressive, severe increases help maintain normophosphatemia despite declining nephron mass. Preliminary data from our group suggest that increased FGF-23 levels in normophosphatemic CKD patients are also associated with coronary artery calcification, left ventricular hypertrophy, and mortality. Importantly, FGF-23 levels rise long before hyperphosphatemia first develops and can be lowered with routine clinical interventions such as dietary phosphorus restriction and phosphorus binders. Thus, we hypothesize that FGF-23 excess is a modifiable risk factor for adverse outcomes in CKD and a novel biomarker to help guide phosphate reduction strategies in normophosphatemic CKD patients who are not currently treated. Our experienced investigative team will study FGF-23 excess as a novel risk factor for adverse cardiovascular and renal outcomes in the Chronic Renal Insufficiency Cohort, an NIH-supported prospective study of 3800 predialysis CKD patients, the vast majority of whom have normal serum phosphate levels. The results could suggest a major paradigm shift for clinical practice with public health implications: phosphate reduction strategies for far more people far earlier in their course of CKD. [unreadable] [unreadable] [unreadable]